1. Field of the Invention
The present invention relates to a compound which can pass through the blood-brain barrier (BBB) carrying a drug and release the drug while being retained in brain, and to its use.
2. Background Art
Cerebral tissue or cells are separated from blood by very tightly combined cerebral capillary vessels (blood-brain barrier), that is, brain is protected by the strict limitation of the interchange of materials through the blood-brain barrier. Therefore, a drug administered systemically sometimes cannot successfully be delivered to brain being impeded by BBB.
In general, the permeability of materials through BBB is correlated with the lipophilicity of the materials. Thus, some lipophilic prodrugs have been synthesized for the purpose of facilitation of delivery to brain of a drug which is hard to permeate through BBB. On the other hand, brain also possesses a mechanism for active excretion of waste materials and drugs back to the periphery. Therefore, it is considered that the conventional prodrugs which only facilitate their distribution to brain by mainly an increase in the lipophilicity have limitations in maintaining the concentration and efficacy of the drug (Rahimy, M. H., et al., Pharm. Res., 10 (1990) 1061-1067). In other words, it is required to provide a means to enhance the transport of the drug across BBB and to prolong the residence in brain of the drug in order to maintain its efficacy following intravenous administration of a drug.
In order to solve the problem, Bodor (Florida University) has proposed a dihydropyridine prodrug which utilizes the NAD+-NADH redox system (Bodor, N., et. al., Science, 214 (1981) 1370-1372). The lipophilic derivative, when incorporated into cells, is oxidized mainly by the NAD.sup.+ oxidation system into a pyridinium cation and retained in brain due to the decrease of its permeability through biological membrane. This method is believed an excellent system for delivering drugs to brain, since the pyridinium cation carrying the drug releases it in a sustained manner. Bodor and his co-workers have already demonstrated the excellence of the method in more than twenty compounds (drugs). However, the dihydropyridine derivative is easily oxidized per se and thus is likely to lead to the deterioration of the quality for example by air oxidation after its synthesis.
The present inventors have examined further possibilities for obtaining the compounds which can pass through BBB and deliver a drug into brain. As a result, we have found that certain kinds of compounds have an excellent property as a carrier for delivering drugs into brain. Thus we have accomplished the present invention.